Modified release preparations containing oxcarbazepine and derivatives thereof

ABSTRACT

Controlled-release preparations of oxcarbazepine and derivatives thereof for once-a-day administration are disclosed. The inventive compositions comprise solubility- and/or release enhancing agents to provide tailored drug release profiles, preferably sigmoidal release profiles. Methods of treatment comprising the inventive compositions are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.17/081,383, filed Oct. 27, 2020, which is a Continuation of U.S.application Ser. No. 16/252,106, filed Jan. 18, 2019, which is aContinuation of U.S. application Ser. No. 15/834,401, filed Dec. 7,2017, now U.S. Pat. No. 10,221,042, which is a Continuation of U.S.application Ser. No. 15/166,816, filed May 27, 2016, now U.S. Pat. No.9,855,278, which is a Continuation of U.S. application Ser. No.14/836,179, filed Aug. 26, 2015, now U.S. Pat. No. 9,351,975, which is aContinuation of U.S. application Ser. No. 14/445,233, filed Jul. 29,2014, now U.S. Pat. No. 9,119,791, which is a Continuation of U.S.application Ser. No. 14/103,103, filed Dec. 11, 2013, now U.S. Pat. No.8,821,930, which is a Continuation of U.S. application Ser. No.13/476,337, filed May 21, 2012, now U.S. Pat. No. 8,617,600, which is aContinuation of U.S. application Ser. No. 13/137,382, filed Aug. 10,2011, now U.S. Pat. No. 8,211,464, which is a Divisional of U.S.application Ser. No. 12/230,275, filed Aug. 27, 2008, now U.S. Pat. No.8,017,149, which is a Continuation of U.S. application Ser. No.11/734,874, filed Apr. 13, 2007, now U.S. Pat. No. 7,722,898, whichclaims priority to U.S. Provisional Application No. 60/794,837, filedApr. 26, 2006.

FIELD OF THE INVENTION

The present invention is directed to controlled-release preparations ofoxcarbazepine and derivatives thereof for once-a-day administration.

BACKGROUND OF THE INVENTION

Oxcarbazepine belongs to the benzodiazepine class of drugs and isregistered worldwide as an antiepileptic drug. Oxcarbazepine is approvedas an adjunct or monotherapy for the treatment of partial seizures andgeneralized tonic-clonic seizures in adults and children. Animmediate-release (IR) formulation of oxcarbazepine is currently on themarket under the trade name Trileptal® and is administered twice a dayto control epileptic seizures. Such immediate release compositionsprovide the drug to the patient in a manner that result in a rapid riseof the plasma drug concentration followed by a rapid decline. This sharprise in drug concentration can result in side effects, and make multipledaily administration of the drug necessary in order to maintain atherapeutic level of the drug in the body. The need for acontrolled-release dosage form for drugs taken chronically such asoxcarbazepine and derivatives is self-evident. Patient compliance isgreatly improved with controlled-release (CR) dosage forms that aretaken, for example, once-a-day. Also, there are significant clinicaladvantages such as better therapeutic efficacy as well as reduced sideeffects with controlled-release dosage forms.

Oxcarbazepine and its derivatives contemplated in this invention arepoorly soluble in water. Due to their poor solubility, their releasefrom a sustained release dosage form is rather incomplete. Whereas thein vitro release of oxcarbazepine is dependent on the dissolutionmethod, including the dissolution media used, it has been found throughin silico modeling that the release of oxcarbazepine in vivo from atraditional sustained-release dosage form is relatively low. Thisresults in reduced bioavailability of the drug making the dosage formineffective in providing a therapeutically effective concentration inthe body. This poses a serious challenge to the successful developmentof sustained-release dosage forms for oxcarbazepine and its derivatives.

The rate of drug release from a dosage form has a significant impact onthe therapeutic usefulness of the drug and its side effects. Hence, drugrelease profiles must be customized to meet the therapeutic needs of thepatient. An example of a customized release profile is one that exhibitsa sigmoidal release pattern, characterized by an initial slow releasefollowed by fast release which is then followed by slow release untilall of the drug has been released from the dosage form.

Sustained-release dosage forms for oxcarbazepine and derivatives havebeen described in the art. For example, Katzhendler et al. (U.S. Pat.No. 6,296,873) describes sustained-release delivery systems forcarbamazepine and its derivatives. Katzhendler et al. teaches that azero-order release profile is achieved for carbamazepine and derivativesthrough the use of hydrophilic and hydrophobic polymers. Zero-order(constant) release was achieved using high molecular weighthydroxypropyl methyl cellulose (HPMC) along with some optionalhydrophobic excipients. A similar approach is taught by Shah et al. (USPatent Application 20020169145). Franke et al. (US Patent Application20040142033) discloses sustained-release formulations of oxcarbazepinethat are characterized by the release of 55%-85% of the drug in 15minutes, and up to 95% in 30 minutes. According to the authors, suchrelease profiles provide adequate sustained-release to achieveonce-a-day administration of oxcarbazepine. However, the solubility andbioavailability of the drug from these enhanced preparations suitablefor once-a-day administration. The prior art does not teach how to makepreparations of oxcarbazepine and derivatives characterized by sigmoidalrelease profiles.

SUMMARY OF THE INVENTION

It is an object of this invention to provide controlled-releaseformulations of oxcarbazepine for once-a-day administration. Thecomposition of this invention is administered once-a-day and yet meetsthe therapeutic need of the patient. It is another object of thisinvention to improve the bioavailability of oxcarbazepine andderivatives thereof. It is yet another object of this invention to meetthe therapeutic need of the patient without causing “spikes” in blooddrug concentration that may lead to toxicity. It is yet another objectof this invention to keep the blood concentration of the drug within thetherapeutic window. It is yet another object of this invention tominimize the fluctuation between the C_(max) and C_(min) that is typicalof many immediate-release and sustained-release preparations.

Many, if not all, of these objectives may be achieved in this inventionthrough formulations that comprise both solubility-enhancing agents andrelease-promoting agents, and are characterized by release profiles thatmeet the requirement for once-a-day administration. The objectives mayalso be achieved through the combination of a multiplicity of units withdifferent release profiles in one dosage unit.Minipellets/granules/tablets, which can be mixed in a certain ratio,provide a dosage form that meets the above stated therapeuticobjectives.

This invention also pertains to multi-layer tablets. Multi-layer tabletscan be prepared with each layer releasing the drug at a rate that isdifferent from the rate of release from another layer. In multi-layertablets, each layer may or may not be coated.

All of the advantages that stem from once-daily administration of a drugapply to the compositions of this invention. Some of the specificadvantages of this invention may be: reduced fluctuation between C_(max)and C_(min) during the course of treatment and hence better therapeuticprofile, reduced side-effects, improved patient compliance, and improvedbioavailability of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles for the three exemplary (CR-F,CR-M, and CR-S) oxcarbazepine formulations containing nosolubility/release enhancer. The profiles show a non-zero order releasewith a lag. The T₈₀s (time for 80% of the dose to be released in vitro)for the CR-F, CR-M, and CR-S formulations were 2 Hrs, 5 Hrs and 11 Hrs,respectively. USP Apparatus II at 60 RPM was used. Dissolution mediumwas 1% SLS in water.

FIG. 2 shows the human pharmacokinetic (PK) profiles with respect tooxcarbazepine for the three exemplary controlled-release formulations ofexample 1 versus an immediate-release reference product (Trileptal® 600mg). The strength of each formulation is 600 mg oxcarbazepine pertablet.

FIG. 3 shows the PK profiles with respect to the metabolite ofoxcarbazepine (MHD) for the three exemplary controlled-releaseformulations of example 1 versus an immediate-release reference product(Trileptal® 600 mg). The strength of each formulation is 600 mgoxcarbazepine per tablet.

FIG. 4 shows the solubility results of oxcarbazepine with selectedexcipients.

FIG. 5 shows the dissolution profiles of oxcarbazepine CR formulationswith solubility enhancer (CRe), without solubility enhancer (CR) and a“fast formulation” (CR-F) developed in Example 1. The time to dissolve80% of the drug (T₈₀) for CRe, CR, and CR-F are 5-6 Hrs, 8 Hrs, and 1.5Hrs, respectively.

FIG. 6 shows the dissolution profiles for the fast (CRe-F), medium(CRe-M), and slow (CRe-S) oxcarbazepine formulations containingsolubility/release enhancers. The T₈₀s for the CRe-F, CRe-M, and CRe-Sare 1.5 Hrs, 5 Hrs, and 8 Hrs, respectively. USP Apparatus II at 60 RPMwas used. Dissolution medium was 1% SLS in water.

FIG. 7 shows the canine pharmacokinetic profiles with respect tooxcarbazepine, comparing the enhanced formulation (CRe) withnon-enhanced formulations containing oxcarbazepine (CR and CR-F).

FIG. 8 shows the canine pharmacokinetic profiles with respect to MHD,comparing the enhanced formulation (CRe) with non-enhanced formulationscontaining oxcarbazepine (CR and CR-F).

FIG. 9 shows the PK profiles shown in FIG. 8 with in silico predicted PKprofile for a twice-a-day 300 mg IR.

FIG. 10 shows in silico predicted PK profiles for various in vitrorelease profiles.

FIG. 11 shows the in silico predicted in vivo release profiles for thesystems in FIG. 10.

FIG. 12 shows human plasma concentration vs. time profiles with respectto MHD of the three Oxcarbazepine CR formulations in Example 4 (CRe-F,CRe-M, CRe-S) and Trileptal® as an IR control, dosed BID.

FIG. 13 shows human plasma concentration vs. time profiles with respectto the oxcarbazepine of the three Oxcarbazepine CR formulations inExample 4 (CRe-F, CRe-M, CRe-S) and Trileptal® as an IR control, dosedBID.

FIG. 14 shows the in silico predicted steady-state plasma profiles forthe three exemplary formulations (CRe-F, CRe-M, and CRe-S) described inExample 4.

DETAILED DESCRIPTION OF THE INVENTION

It is the object of this invention to provide controlled-releaseoxcarbazepine formulations suitable for once-a-day administration. It isan additional object of the invention to incorporate a combination ofsolubility-enhancing excipients and/or release-promoting agents into theformulations to enhance the bioavailability of oxcarbazepine and itsderivatives. Such compositions are referred to as enhanced formulations.

Oxcarbazepine was formulated to provide release profiles characterizedby slow release initially, followed by rapid release and then followedby another period of slow release. Such a release profile is known tothose skilled in the art as sigmoidal. Oxcarbazepine formulations withsigmoidal release profiles were tested in human pharmacokinetic (PK)studies. Based on the human data, improvements were made to theformulations by incorporating solubility enhancers and/orrelease-promoting excipients (such formulation are referred to asenhanced formulations). The enhanced formulations were tested in caninemodels and were surprisingly found to provide significant increase inbioavailability of oxcarbazepine compared to formulations containing nosolubility/release enhancing excipients.

The incorporation of solubility enhancing agents in formulationscontaining poorly soluble drugs such as oxcarbazepine has a profoundeffect on the in vivo solubility and hence bioavailability of the drugs.Enhancing the solubility of oxcarbazepine results in an increase in itsbioavailability and hence in better therapeutic performance of the drug.A combination of solubility and release promoters is contemplated inthis invention. Preferable release promoting agents are pH dependentpolymers, also known as enteric polymers. These materials are well knownto those skilled in the art and exhibit pH dependent solubility suchthat they dissolve at pH values higher than about 4.0, while remaininginsoluble at pH values lower than 4.0. Solubilizers function byincreasing the aqueous solubility of a poorly soluble drug. When aformulation containing both the enteric polymer and solubilizer isexposed to an aqueous media of pH higher than 4.0, the enteric polymerdissolves rapidly leaving a porous structure, resulting in increasedcontact surface between the aqueous medium and the poorly soluble drug.This increased surface area enhances the efficiency of thesolubilizer(s), and hence, the overall solubility and release rate ofthe drug is enhanced to a point where it impacts the availability of thedrug for systemic absorption in patients.

Excipients that function as solubility enhancers can be ionic andnon-ionic surfactants, complexing agents, hydrophilic polymers, pHmodifiers, such as acidifying agents and alkalinizing agents, as well asmolecules that increase the solubility of poorly soluble drug throughmolecular entrapment. Several solubility enhancers can be utilizedsimultaneously. All enteric polymers that remain intact at pH valuelower than about 4.0 and dissolve at pH values higher than 4.0,preferably higher than 5.0, most preferably about 6.0, are considereduseful as release-promoting agents for this invention.

Suitable pH-sensitive enteric polymers include cellulose acetatephthalate, cellulose acetate succinate, methylcellulose phthalate,ethylhydroxycellulose phthalate, polyvinylacetate phthalate,polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer,styrene-maleic monoester copolymer, methyl acrylate-methacrylic acidcopolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, etc.These may be used either alone or in combination, or together with thepolymers other than those mentioned above. Preferred enteric polymersare the pharmaceutically acceptable methacrylic acid copolymers. Thesecopolymers are anionic polymers based on methacrylic acid and methylmethacrylate and, preferably, have a mean molecular weight of about135000. A ratio of free carboxyl groups to methyl-esterified carboxylgroups in these copolymers may range, for example, from 1:1 to 1:3, e.g.around 1:1 or 1:2. Such polymers are sold under the trade name Eudragit™such as the Eudragit L series e.g. Eudragit L 12.5™, Eudragit L 12.5P™,Eudragit L100™, Eudragit L 100-55™, Eudragit L-30D™, Eudragit L-30D-55™, the Eudragit S™ series e.g. Eudragit S 12.5™, Eudragit S 12.5P™,Eudragit S100™. The release promoters are not limited to pH dependentpolymers. Other hydrophilic molecules that dissolve rapidly and leachout of the dosage form quickly leaving a porous structure can be also beused for the same purpose.

The release-promoting agent can be incorporated in an amount from 10% to90%, preferably from 20% to 80% and most preferably from 30% to 70% byweight of the dosage unit. The agent can be incorporated into theformulation either prior to or after granulation. The release-promotingagent can be added into the formulation either as a dry material, or itcan be dispersed or dissolved in an appropriate solvent, and dispersedduring granulation.

Solubilizers preferred in this invention include surface active agentssuch as sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate,Tweens® and Spans (PEO modified sorbitan monoesters and fatty acidsorbitan esters), poly(ethylene oxide)-polypropylene oxide-poly(ethyleneoxide) block copolymers (aka Pluronics™); complexing agents such as lowmolecular weight polyvinyl pyrrolidone and low molecular weighthydroxypropyl methyl cellulose; molecules that aid solubility bymolecular entrapment such as cyclodextrins, and pH modifying agents,including acidifying agents such as citric acid, fumaric acid, tartaricacid, and hydrochloric acid; and alkalizing agents such as meglumine andsodium hydroxide.

Solubilizing agents typically constitute from 1% to 80% by weight,preferably from 1% to 60%, more preferably from 1% to 50%, of the dosageform and can be incorporated in a variety of ways. They can beincorporated in the formulation prior to granulation in dry or wet form.They can also be added to the formulation after the rest of thematerials are granulated or otherwise processed. During granulation,solubilizers can be sprayed as solutions with or without a binder.

This invention also contemplates controlled-release formulationscomprising oxcarbazepine that release the drug at variable rates in theGI tract. It is also an object of this invention to design a drugdelivery system to deliver drug at a very low rate early, followed by arelatively increased rate. It is another object of this invention toprovide a drug release profile that is characterized by animmediate-release followed by a modified-release, such asextended-release (XR) or delayed-release (DR). These types of releaseprofiles ensure that the C_(max) (maximum concentration of the drug inblood/plasma) is kept within the therapeutic window while extending themaintenance of an effective drug level in the body. The goal of thisinvention is to develop a controlled-release pharmaceutical compositionof oxcarbazepine that provides steady-state blood levels of MHD, anactive metabolite of oxcarbazepine, at a concentration of about 2 μg/mlto about 10 μg/ml. In the preferred embodiment, steady-state bloodC_(max) levels of MHD fall in the range of about 6 μg/ml to about 10μg/ml, and C_(min) levels of MHD fall in the range of about 2 μg/ml toabout 5 μg/ml. Reduced fluctuation between C_(max) and C_(min) duringthe course of treatment results in a better therapeutic profile, reducedside-effects, improved patient compliance, and improved bioavailabilityof the drug.

The desired drug release pattern contemplated by this invention isachieved by using “matrix” polymers that hydrate and swell in aqueousmedia, such as biological fluids. As these polymers swell, they form ahomogenous matrix structure that maintains its shape during drug releaseand serves as a carrier for the drug, solubility enhancers and/orrelease promoters. The initial matrix polymer hydration phase results inslow-release of the drug (lag phase). Once the polymer is fully hydratedand swollen, the porosity of the matrix increases due to the leachingout of the pH-dependent release promoters, and drug is released at afaster rate. The rate of the drug release then becomes constant, and isa function of drug diffusion through the hydrated polymer gel.

Thus, the release vs. time curve is characterized by at least twoslopes: one slope for the lag phase where drug release rate is low and asecond slope where drug release is faster. The slope of the rising partof the release vs. time curve can be customized as to match the rate atwhich the drug is eliminated from the body. A desired release profilecan be achieved by using swellable polymers alone or in combination withbinders, such as gelling and/or network forming polymers.

The water-swellable, matrix forming polymers useful in the presentinvention are selected from a group comprising cellulosic polymers, suchas hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulosesuch as microcrystalline cellulose, cellulose acetate, sodiumcarboxymethylcellulose, calcium salt of carboxymethylcellulose, andethylcellulose; alginates, gums such as guar and xanthan gums;cross-linked polyacrylic acid derivatives such as Carbomers (akaCarbopol™) available in various molecular weight grades from Noveon Inc.(Cinncinatti, Ohio); carageenan; polyvinyl pyrrolidone and itsderivatives such as crospovidone; polyethylene oxides; and polyvinylalcohol. Preferred swellable polymers are the cellulosic compounds, HPMCbeing the most preferred.

The swellable polymer can be incorporated in the formulation inproportion from 1% to 50% by weight, preferably from 5% to 40% byweight, most preferably from 5% to 20% by weight. The swellable polymersand binders may be incorporated in the formulation either prior to orafter granulation. The polymers can also be dispersed in organicsolvents or hydro-alcohols and sprayed during granulation.

It is yet another aspect of this invention to prepare formulations ofoxcarbazepine that combine multiple modified-release “units,” each“unit” prepared according to any one or more of the above-discloseddosage forms, to provide for a customized release profile.

The modified-release units comprise minipellets/granules/tablets etc.,each with unique release profiles, that can be mixed in a certain ratioto provide a dosage form that meets the above-stated therapeuticobjectives. Alternatively, multiple modified release units may be formedinto of multi-layer tablets. Multi-layer tablets can be prepared witheach layer releasing the active compound at a rate that is differentfrom the rate of release of the active ingredient from another layer. Inmulti-layer tablets, each layer may optionally be coated withcontrolled-release polymer(s). The combination dosage forms can exhibitrelease profiles that comprise any/all possible combinations ofimmediate release (IR), delayed release (DR), and extended release (XR)formulations. Pellets/granules/tablets or each layer of a single tabletmay optionally be coated.

Various hydrophobic excipients can be used to modify the hydration rateof the dosage unit when exposed to water or aqueous media. Theseexcipients retard the wetting of the dosage unit and hence modify therelease of the active agent. Hydrophobic excipients suitable for thisinvention are represented by, but not limited to, glyceryl monstearate,mixtures of glyceryl monostearate and glyceryl monopalmitate (Myvaplex,Eastman Fine Chemical Company), glycerylmonooleate, a mixture of mono,di and tri-glycerides (ATMUL 84S), glycerylmonolaurate, glycerylbehenate, paraffin, white wax, long chain carboxylic acids, long chaincarboxylic acid esters and long chain carboxylic acid alcohols.

Examples of saturated straight chain acids, useful with the invention,are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid,caproic acid, caprylic acid, capric acid, lauric acid, myristic acid,palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acidand melissic acid. Also useful are unsaturated monoolefinic straightchain monocarboxylic acids. Examples of these are oleic acid, gadoleicacid and erucic acid. Also useful are unsaturated (polyolefinic)straight chain monocarboxylic acids such as linoleic acid, linolenicacid, arachidonic acid and behenolic acid. Useful branched acidsinclude, for example, diacetyl tartaric acid.

Examples of long chain carboxylic acid esters include, but are notlimited to: glyceryl monostearates; glyceryl monopalmitates; mixtures ofglyceryl monostearate and glyceryl monopalmitate (Myvaplex 600, EastmanFine Chemical Company); glyceryl monolinoleate; glyceryl monooleate;mixtures of glyceryl monopalmitate, glyceryl monostearate, glycerylmonooleate and glyceryl monolinoleate (Myverol 18-92, Eastman FineChemical Company); glyceryl monolinoleate; glyceryl monogadoleate;mixtures of glyceryl monopalmitate, glyceryl monostearate, glycerylmonooleate, glyceryl monolinoleate, glyceryl monolinoleate and glycerylmonogadoleate (Myverol 18-99, Eastman Fine Chemical Company); acetylatedglycerides such as distilled acetylated monoglycerides (Myvacet 5-07,7-07 and 9-45, Eastman Fine Chemical Company); mixtures of propyleneglycol monoesters, distilled monoglycerides, sodium stearoyl lactylateand silicon dioxide (Myvatex TL, Eastman Fine Chemical Company);mixtures of propylene glycol monoesters, distilled monoglycerides,sodium stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman FineChemical Company), d-alpha tocopherol polyethylene glycol 1000 succinate(Vitamin E TPGS, Eastman Chemical Company); mixtures of mono- anddiglyceride esters such as Atmul (Humko Chemical Division of WitcoChemical); calcium stearoyl lactylate; ethoxylated mono- anddi-glycerides; lactated mono- and di-glycerides; lactylate carboxylicacid ester of glycerol and propylene glycol; lactylic esters of longchain carboxylic acids; polyglycerol esters of long chain carboxylicacids, propylene glycol mono- and di-esters of long chain carboxylicacids; sodium stearoyl lactylate; sorbitan monostearate; sorbitanmonooleate; other sorbitan esters of long chain carboxylic acids;succinylated monoglycerides; stearyl monoglyceryl citrate; stearylheptanoate; cetyl esters of waxes; cetearyl octanoate; C₁₀-C₃₀cholesterol/lavosterol esters; and sucrose long chain carboxylic acidesters. In addition, waxes can be useful alone or preferably incombination with the materials listed above. Examples of these are whitewax, paraffin and carnauba wax.

Drug, polymers, and other excipients are typically combined and wetgranulated using a granulating fluid. However, other methods of forminggranules such as slugging, and roller compaction can also be used tomanufacture matrix granules. Matrix tablets can also be made by directcompression. In wet granulation, typical granulating fluids are: water,a mixture of water and alcohol, anhydrous alcohol. Wet granules can bemade in any granulating device such as mixers, high shear granulators,and fluid bed granulators. Granules can be dried in appropriate dryingequipment such as fluid bed dryers, ovens, microwave dryers etc.Granules can also be air-dried. Dried granules can be milled usingappropriate milling device to achieve a particular particle sizedistribution. Granules can be filled in to capsules, or blended withother excipients and tableted on a tablet press. Granules can also bepackaged into sachets for sprinkle application. Other excipients used toaid tableting are well known to those skilled in the art and includemagnesium stearate, talc, cabosil etc. Granules and tablets can,optionally, be coated to further modify release rates. Furthermore,formulations can also optionally contain dyes.

Optionally, but preferably, the tablet composition can contain one ormore lubricants, which may be added to assure proper tableting.Non-limiting examples of lubricants include magnesium stearate, calciumstearate, zinc stearate, stearic acid, polyethylene glycol, leucine,glyceryl behenate, sodium stearyl fumarate, hydrogenated vegetable oils,and other waxes, including but not limited to, beeswax, carnuba wax,cetyl alcohol, glyceryl stearate, glyceryl palmitate, and stearylalcohol. The lubricant, when present, is typically included in an amountof from about 0.1 wt. % to about 20 wt. % of the composition, preferablyfrom about 1 to about 10 wt. %, and more preferably about 0.3 to about3.0 wt. %.

The oxcarbazepine dosage can be formulated into tablets, granules, andpellets. The steps involved in the manufacturing of these dosage formsare well known to those skilled in the art. Briefly, tablets can becompressed from directly compressible blend containing the active orpre-formed granules. The tablets can be coated or not coated. Thecoating may optionally impart modification of release. Granules can bemade by high shear granulation or fluid bed processing. The granules mayor may not be coated. Pellets can be manufactured by drug layering oninert carriers such as sugar spheres. Pellets can also be manufacturedby extrusion/spheronization process. The pellets may or may not becoated. Coated pellets and granules can be filled into capsules.

Formulations of this invention can also be made in pelletized forms,which can be filled into capsules or dispensed in sachets for sprinkleapplication. Each pellet is composed of the drug, swellable polymer(s)and other excipients that aid the processing. Pellets can be prepared inone of the many ways that are known by those skilled in the art. Theseinclude, for example, extrusion/spheronization and roller compaction(slugging). In the extrusion/spheronization technique, drug is mixedwith swellable polymer(s), such as cellulosic polymers and otherexcipients. The blend is then granulated in a high shear granulator. Thewet mass is then passed through an extruder and spheronized using aspheronizer. The pellets are then dried in an oven or fluid bedprocessor. The dried pellets are either processed further orencapsulated without further processing.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and notintended to be limiting.

The invention now will be described in particularity with the followingillustrative examples; however, the scope of the present invention isnot intended to be, and shall not be, limited to the exemplifiedembodiments below.

EXAMPLES Example 1. Oxcarbazepine Formulations with Sigmoidal ReleaseProfiles

Table 1 provides the formula composition of oxcarbazepinecontrolled-release preparations with sigmoidal release profiles.Granules were prepared by high shear granulation using anhydrous ethanolas the granulating liquid. All ingredients, except for magnesiumstearate, were charged in to VG-65/10M high shear granulator. The drypowders are blended by running the blade for 3 minutes, after which timethe anhydrous ethanol was sprayed onto the mixing blend at a spray rateof approximately 40-60 gm/min. After about a minute of spray, thechopper on the VG-65/10M was started and run throughout the spray. Oncethe granulation was completed, the granulation was discharged from theVG high shear granulator, spread on an appropriate tray and placed in anoven to dry at 40° C. for 24 Hrs. Alternatively, granules can be driedusing a fluid bed processor. Dry granules were screened through an18-mesh screen. Screened granules were blended with magnesium stearatein a proportion of 99.5% granules and 0.5% magnesium stearate. The blendwas then tableted on a rotary tablet press.

TABLE 1 Formula composition of Oxcarbazepine CR formulations withchanging slope SLI 530 CR-F SLI530 CR-M SLI530 CR-S Ingredients (Fast)(Medium) (Slow) Oxcarbazepine 60 60 60 Compritol 888ATO 9.5 7 — ProsolvHD90 9.8 20.3 15 Kollidon 25 10 — — Kollidon 90 — 3 — Methocel E5 Prem.— — 10 LV Methocel K4M — — 5 Premium CR Carbopol 971P 10 9 9 Mg Stearate0.5 0.5 0.5 FD&C Red #40 — — 0.5 FD&C Blue #1 0.2 — — FD&C Yellow #6 —0.2 — Anhydrous Ethanol * * * Total 100 100 100 * Removed duringprocessing

FIG. 1 shows the dissolution profiles of three exemplary oxcarbazepineCR formulations (CR-F, CR-M, and CR-S). The profiles exhibited non-zeroorder release.

Example 2. Human Pharmacokinetic Evaluation of Oxcarbazepine CRFormulations from Example 1

The three formulations from the Example 1 were evaluated in humans toobtain pharmacokinetic information. An immediate release tablet(Trileptal® 600 mg) was used as a control reference. The formulationswere examined in a randomized, single dose, crossover study in healthyhuman volunteers. Blood samples were analyzed for both the parentmolecule oxcarbazepine and its metabolite (the monohydroxy derivative,MHD).

Table 2 provides the mean PK parameters for MHD. The PK profiles areshown in FIGS. 2 and 3.

TABLE 2 Pharmacokinetic parameters of the three exemplary formulationsin example 1 and immediate release reference product. CR-F CR-M CR-STrileptal ™ PK Parameters Fast Med Slow IR T_(max) (Hr) 6.5 8.4 9.1 1.4C_(max) (ug/mL) 0.248 0.146 0.103 1.412 AUC_(last) (Hr*ug/mL) 3.0 2.51.7 5.7 Rel BA 53% 44% 30% 100%

Example 3. Solubility Enhancers Screening

The solubility of oxcarbazepine in the presence of excipients wasevaluated as follows:

Excipients were dissolved in phosphate buffer to make solutions withconcentrations shown in Table 3. One gram of oxcarbazepine was thenmixed with 19 gm of the excipient solution. The mixture was rockedovernight at room temperature and then filtered using 0.22 μm filter.The filtrates were analyzed by HPLC. The solubility results are given inTable 3 and FIG. 4.

TABLE 3 Solubility of Oxcarbazepine in the presence of excipientsExcipient conc. Solubility Excipients (% w/w) (mg/mL) Phosphate BufferControl NA 0.4009 Hydroxypropyl 5 1.0218 betacyclodextrin (HBCD) SodiumLauryl Sulfate (SLS) 5 4.1113 Kollidon 17 1 0.1717 SLS/HBCD 1, 1 0.3489Cremophor RH40 1 0.3140 Docusate Sodium 5 6.5524 SLS/Polyethylene Glycol400 5, 1 3.0516 (PEG400) SLS/Stearic Acid/PEG400 5, 1, 1 3.2821De-ionized Water NA 0.2733

Example 4. Formulation of Enhanced Dosage Forms

Tables 4 and 5 provide the composition of the formulation containingsolubility- and release-enhancing agents. Granules were manufactured byhigh shear granulation using water as the granulating liquid. Allingredients, except for magnesium stearate, were charged into aVG-65/10M high shear granulator. The dry powders were blended by runningthe blade for 3 minutes, upon which time water was sprayed onto themixing blend at a spray rate of approximately 40-60 gm/min. After abouta minute of spray, the chopper on the VG-65/10M was started and runthroughout the spray. Once the granulation was completed, thegranulation was discharged from the VG high shear granulator, spread onan appropriate tray and placed in an oven to dry at 40° C. for 24 Hrs.Alternatively, granules can be dried using a fluid bed processor. Drygranules are screened through an 18-mesh screen. Screened granules wereblended with magnesium stearate in a proportion of 99.5% granules and0.5% magnesium stearate. The resulting blend was then tableted on arotary tablet press. Dissolution profiles for these formulations areshown in FIGS. 5 and 6.

TABLE 4 Percent Composition of Enhanced (CRe-M) and non-Enhanced (CR)Prototypes % PD0294-005 % PD0294-008 Formulation Enhanced Non-EnhancedOxcarbazepine 60 60 Prosolv SMCC50 10 25 PVP K25 5 5 HPMC K4M premium 1010 SLS 5 0 Eudragit L100-55 10 0 Magnesium Stearate 0.5 0.5

TABLE 5 Percent Composition for the three exemplary enhancedformulations: CRe-F, CRe-M, and CRe-S. % PD0294-046 % PD0294-051 %PD0294-054 Formulation CRe-F CRe-M CRe-S Oxcarbazepine 60 60 60 ProsolvSMCC50 15 10 5 PVP K25 5 5 5 HPMC K4M premium 5 10 15 SLS 5 5 5 EudragitL100-55 10 10 10 Magnesium Stearate 0.5 0.5 0.5

Example 5. Canine PK Studies on Formulations from Example 4, Table 4 andExample 1. (SLI530CR-F)

Six male beagle dogs were dosed orally with the formulations in theorder given in Table 6. Blood was drawn over a 24 Hr period and bloodsamples were analyzed by HPLC. A noncompartmental analysis of the datawas used to generate T_(max), C_(max), AUC_(last), and AUC_(inf).Relative Bioavailability was calculated in Excel using the AUC_(last)and AUC_(inf) for the CRf formulation as the control. The PK profilesfor oxcarbazepine and 10-hydroxycarbazepine are given in FIGS. 7 and 8.

TABLE 6 Prototypes tested in dogs Phase Test Article SLI Lot # Dose (mg)1 Oxcarbazepine CR PD0294-024A 600 2 Oxcarbazepine CRe PD0294-024B 600 3Oxcarbazepine CR-F B04032 600

TABLE 7 Canine pharmacokinetic profiles for enhanced, non- enhanced andcontrol formulations of oxcarbazepine Non-Enhanced Enhanced CR Fast CRCR (CR) (CRe-M) (CR-F) Prototypes PD0294-024A PD0294-024B B04032 T_(max)1.5 1.8 1.7 C_(max) 1.20 1.72 0.7 AUC_(last) 3.44 7.98 3.41 AUC_(inf)3.74 11.09 4.01 Rel BA_(last) 101% 234% 100% Rel BA_(inf)  93% 276% 100%

Example 6 in Silico Modeling of Various Release Profiles ofOxcarbazepine XR

In silico modeling was carried out for various hypothetical systems.Results are shown in FIGS. 9-11.

Example 7. Human Pharmacokinetic Evaluation of Solubility EnhancedOxcarbazepine CR Formulations from Example 4

The three solubility enhanced prototypes from the Example 4 wereevaluated in humans to obtain pharmacokinetic information. An immediaterelease tablet (Trileptal® 300 mg) given BID was used as a reference.The formulations were examined in a randomized, single dose, crossoverstudy in healthy human volunteers. Blood samples were analyzed for boththe parent molecule oxcarbazepine and its metabolite (the monohydroxyderivative, MHD).

Table 8 provides the mean PK parameters for MHD. The PK profiles areshown in FIGS. 12 and 13.

TABLE 8 Pharmacokinetic parameters of the three exemplary solubilityenhanced formulations in Example 4 and Trileptal ™ CRe-F CRe-M CRe-STrileptal ™ PK Parameters Fast Med Slow BID T_(max) (Hr) 9 11 14 16C_(max) (ug/mL) 5.32 5.14 4.40 6.23 AUC_(last) (Hr*ug/mL) 160.3 161.3148.9 167.1 Rel BA 96% 97% 89% 100%

What is claimed is:
 1. A controlled-release formulation comprising (a)oxcarbazepine, (b) a matrix-forming polymer selected from the groupconsisting of cellulosic polymers, alginates, gums, cross-linkedpolyacrylic acid, carageenan, polyvinyl pyrrolidone, polyethyleneoxides, and polyvinyl alcohol, and (c) at least one agent that enhancesthe solubility of oxcarbazepine.
 2. The formulation of claim 1, whereinthe formulation is effective in minimizing fluctuations between C_(min)and C_(max) of monohydroxy derivative of oxcarbazepine.
 3. Theformulation of claim 1, wherein the amount of oxcarbazepine in thecontrolled release formulation is 600 mg.
 4. The formulation of claim 1,wherein the formulation further comprises (d) a release-promoting agent.5. The formulation of claim 4, wherein the release-promoting agentcomprises a polymer having pH-dependent solubility.
 6. The formulationof claim 4, wherein the release-promoting agent comprises an entericpolymer.
 7. The formulation of claim 1, which can be administered once aday.
 8. The formulation of claim 1, wherein the at least one agent thatenhances the solubility of oxcarbazepine is selected from the groupconsisting of surface active agents, complexing agents, cyclodextrins,pH modifying agents, and hydration promoting agents.